This invention relates to discorhabdin compounds and compositions which have useful therapeutic properties. More particularly, the invention provides discorhabdin compounds having antitumor activities, pharmaceutical compositions comprising such compounds, methods for the preparation of the compounds, and compositions and methods of their use.
Various tumor and cancer related diseases afflict animals, including humans. The term xe2x80x9ctumorxe2x80x9d refers to abnormal masses of new tissue growth which is discordant with the the tissue of origin or of the host""s body as a whole. Tumors inflict animals with a variety of disorders and conditions, including various forms of cancer. The seriousness of cancer is well known, e.g. cancer is second only to heart and vascular diseases as a cause of death in man. Cancer is common in a variety of animals, and the prevention and control of the growth of tumors is important to man.
Considerable research and resources have been devoted to oncology and anticancer measures, including chemotherapy. While certain methods and chemical compositions have been developed which aid in inhibiting, remitting, or controlling unwanted cellular proliferation, further anticancer methods and chemical compositions are needed.
It has been found that some natural products and organisms are potential sources for chemical molecules having useful biological activities. For example, the diterpene commonly known as paclitaxel (Taxol(copyright)), isolated from several species of yew trees, is a mitotic spindle poison that stabilizes microtubules and inhibits their depolymerization to free tubulin (Fuchs, D. A., R. K. Johnson [1978] Cancer Treat. Rep. 62:1219-1222; Schiff, P. B., J. Fant, S. B. Horwitz [19791] Nature (London) 22:665-667). Taxol(copyright) is also known to have antitumor activity and has undergone a number of clinical trials which have shown it to be effective in the treatment of a wide range of cancers (Rowinski, E. K. R. C. Donehower [1995] N. Engl. J. Med. 332:1004-1014). See also, e.g. U.S. Pat. Nos. 5,157,049; 4,960,790; and 4,206,221.
Marine life has been the source for the discovery of compounds having varied biological activities. Some of the United States patents which have issued for such inventions are as follows: U.S. Pat. No. 4,548,814 for didemnins, having antiviral activity, were isolated from a marine tunicate; U.S. Pat. No. 4,729,996 discloses compounds, having antitumor properties, that were isolated from marine sponges Teichaxinella morchella and Ptilocaulis walpersi; U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp.; and U.S. Pat. No. 4,737,510 discloses compounds, having antiviral and antibacterial properties, isolated from the Caribbean sponge Agelas coniferin. 
A number of publications disclose organic compounds derived from marine sponges including Scheuer, P. J. (ed.) Marine Natural Products, Chemical and Biological Perspectives, Academic Press, New York, 1978-1983, Vol. I-V; Uemura, D., K. Takahashi, T. Yamamoto, C. Katayama, J. Tanaka, Y. Okumura, Y. Hirata (1985) J. Am. Chem. Soc. 107:4796-4798; Minale, L. et al. (1976) Fortschr. Chem. org. Naturst. 33:1-72; Faulkner, D. J. (2002) Natural Products Reports 19:1-48; Gunasekera, S. P., M. Gunasekera, R. E. Longley and G. K. Schulte (1990) xe2x80x9cDiscodernolide: A new bioactive polyhydroxy lactone from the marine sponge Discodermia dissolutaxe2x80x9d J. Org. Chem., 55:4912-4915 [correction (1991) J. Org. Chem. 56:1346]; Hung, Deborah T., Jenne B. Nerenberg, Stuart Schreiber (1994) xe2x80x9cDistinct binding and cellular properties of synthetic (+)- and (xe2x88x92) discodermolidesxe2x80x9d Chemistry and Biology 1:67-71; Hung, Deborah T., Jie Cheng, Stuart Schreiber (1996) (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks Taxol binding and results in mitotic arrestxe2x80x9d Chemistry and Biology 3:287-293; Nerenberg, Jennie B., Deborah T. Hung, Patricia K. Somers, Stuart L. Schreiber (1993) xe2x80x9cTotal synthesis of immunosuppressive agent (xe2x88x92)-discodemolidexe2x80x9d J. Amer. Chem. Soc. 115:12621-12622; Smith III, Amos B., Yuping Qiu, David R. Jones, Karoru Kobayashi (1995) xe2x80x9cTotal synthesis of (xe2x88x92) discodernolidexe2x80x9d J. Amer. Chem. Soc. 117:12011-12012; Harried, Scott H., Ge Yang, Marcus A. Strawn, David C. Myles (1997) xe2x80x9cTotal synthesis of (xe2x88x92)-discodermolide: an application of a chelation-controlled alkylation reactionxe2x80x9d J. Org. Chem. 62:6098-6099; Balachandran, R., ter Haar, E., Welsh, M. J., Grant, S. G., and Day, B. W. (1998) xe2x80x9cThe potent microtubule-stabilizing agent (+)-discodermolide induces apoptosis in human breast carcinoma cells-preliminary comparisons to paclitaxel.xe2x80x9d Anticancer Drugs 9: 67-76 and references cited therein. U.S. Pat. No. 4,808,590 discloses compounds, having antiviral, antitumor, and antifungal properties, isolated from the marine sponge Theonella sp. (International Patent Application No. WO 9824429; Kowalski, R. J., P. Giannakakou, S. P. Gunasekera et al. (1997) Mol. Pharmacol 52:613-622; ter Haar, E., R. J. Kowalski, E. Hamelet al. (1996) Biochemistry 35:243-250; Stafford, J. A. and M. M. Mehrotra (1995) Chemtract: Org. Chem. 8:41-47; and U.S. Pat. No. 5,789,605.
Discorhabdin compounds have been produced from marine sponges as disclosed in U.S. Pat. Nos. 4,731,366; 4,874,767; and 6,057,333 and have been discussed in various publications including: Perry, N. B. et al. (1986) J. Org. Chem. 51:5476; Blunt, J. W. et al. (1987) J. Nat. Prod. 50:290; Munro, M. H. G. et al. (1987) Bioorganic Marine Chemistry, Scheuer, P. J., Ed., Verlag Chemie: Heidelberg, Vol. 1, Chapter 4; Kobayashi, J. et al. (1987) Tetrahedron Letters 28:4939; Perry, N. B. et al. (1988) Tetrahedron Letters 44:1727; Perry, N. B. et al. (1988) J. Org. Chem. 53:4127; and Cheng et al. (1988) J. Org. Chem. 53:4610.
The previously known discorhabdins (Axe2x86x92R), have an iminoquinone and a spiro-enone or spiro-dienone system, and are believed to be formed by the combination of a molecule of substituted tyrosine and a molecule of tryptamine.
The present invention, utilizing sponges as a source material, provides the art with new biologically active compounds and new pharmaceutical compositions useful for the control of unwanted cellular proliferation as antitumor agents. The present invention has added to the arsenal of phrmaceutical compounds by the discovery of novel compounds isolatable from extracts of marine sponges of the family Desmacididae.
The subject invention provides discorhabdin compounds having advantageous biological activities. Specifically, in one embodiment, the discorhabdin compounds and compositions of the subject invention can be used in the treatment of an animal (including humans) hosting cancer cells, including, for example, inhibiting the growth of tumor cells in a mammalian host. More particularly, the subject compounds can be used for inhibiting in a human the growth of tumor cells, including cancer cells of the pancreas, breast, colon, CNS, ovarian, renal, prostrate, lung, leukemia and melanoma cells.
Also provided according to the subject invention are compositions containing the biologically active discorhabdin compounds, as well as methods for the preparation and use of the compounds and compositions.
Other advantages and further scope of applicability of the present invention will become apparent from the detailed descriptions given herein; it should be understood, however, that the detailed descriptions, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent from such descriptions.